HIV/AIDS remains a formidable global epidemic with 33 million infections worldwide, including over 1 million patients in the US. In 2008, there were 2.7 million new infections and 2 million AIDS-related deaths. Current HIV treatment combines drugs from several classes of HIV inhibitors and has dramatically extended the lives of many HIV patients, but serious side effects and rapidly increasing drug resistance are significant concerns. Thus, there is a continuing need to develop HIV inhibitors with new mechanisms of action and more robust resistance profiles. Navigen Pharmaceuticals is a pharmaceutical development company targeting infectious diseases. Using a combination of discovery and design, we have identified a novel type of HIV entry inhibitor (protease-resistant D-peptide) that targets HIV's conserved extracellular entry machinery and overcomes the limitations of existing HIV entry inhibitors (e.g., frequent and high dosing, narrow breadth, injection site reactions, and susceptibility to resistance). Our lead prototype (PIE12-trimer) potently inhibits diverse strains from all major subtypes of HIV and is extraordinarily elusive to resistance. We have developed multiple variants of PIE12-trimer in an effort to minimize dosing frequency and have selected two that we expect to be superior. In this one-year grant application, Navigen proposes to (1) develop a bioanalytical assay to support preclinical development of PIE12-trimer, (2) measure pharmacokinetic (PK) properties, and (3) conduct acute, 7-day, and 28-day rat toxicity studies on the two most promising lead candidates. This information will allow Navigen to select an ideal PIE12-trimer variant with low toxicity and PK properties compatible with weekly dosing for advancement into IND-enabling studies and ultimately clinical trials. PUBLIC HEALTH RELEVANCE: Navigen Pharmaceuticals is developing a potent and novel inhibitor of HIV entry. The goal of this study is to optimize our lead candidate for weekly dosing and low toxicity. If successful, this new inhibitor will improve the health of HIV/AIDS patients by providing them with a safe and highly effective new therapeutic option.